Analogs of L-Glu-L-Trp having pharmacological activity

ABSTRACT

This invention provides analogs of L-Glu-L-Trp and methods of using them for immunomodulation and treatment of pathological neovascular conditions. The analogs include the substitution of a carbon atom for a nitrogen atom in the indole ring of tryptophan.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of the U.S.application Ser. No. 08/614,764, filed Jan. 7, 1998, which is continuingprosecution application of Ser. No. 08/614,764, filed Mar. 13, 1996.This application is related to U.S. Pat. No. 5,538,951 and to U.S.application Ser. Nos. 08/452,411, filed May 26, 1995 and 08/415,009,filed Mar. 31, 1995. The above-referenced patents and applications areincorporated herein by reference in their entireties for all purposes.

BACKGROUND OF THE INVENTION

[0002] This invention is directed to the field of pharmaceuticalcompounds and methods of use. In particular, this invention is directedto analogs of the di-peptide, L-Glu-L-Trp in which the nitrogen of theindole ring of tryptophan is substituted with a carbon. These analogshave similar immunomodulating and anti-angiogenic activity to the parentcompound.

[0003] L-Glu-L-Trp, also known as thymogen, is a dipeptide knownnormalize immune system function. The drug was found to be the activeprinciple in an extract of the thymus gland called thymosin. (Morozov etal., U.S. Pat. No. 5,070,076.) The dipeptide has been shown to beeffective in the treatment of immunodeficient, immunodepressed orhyperactive immune states. (Khavinson et al., WO 92/17191; Khavinson etal., WO 95/03067; and Morozov et al., U.S. Pat. No. 5,538,951.)Pro-drugs of L-Glu-L-Trp, such as cyclized versions of the dipeptide orlinear polymers of the dipeptide, are processed by the body into theactive compound. (Khavinson et al., WO 93/08815.) Two related compounds,L-Ile-L-Trp and L-Leu-L-Trp, also have been shown to haveimmunomodulating properties similar to L-Glu-L-Trp. (Khavinson et al.,WO 94/20063.) In addition to these properties, L-Glu-L-Trp hasanti-angiogenic activity. (Green et al., WO 97/12625.)

[0004] Other related compound reported to stimulate the immune responseare the tripeptide Pyr-Leu-Trp and phoshoramidon (sugar-Leu-Trp).(Polita et al., U.S. Pat. No. 5,143,903.) However, there is no report ofthese compounds being tested against HIV infection.

[0005] These tryptophan-containing dipeptides are believed to function,at least in part, by reversibly associating with specific cellularreceptors, namely “CD2” receptors, thereby inducing conformation changesin the receptor which “trigger” intracellular mechanisms resulting inup-regulation of adenylate cyclase and an increase in AMP. Theysimultaneously increase the affinity of the CD2 receptor for its“target” ligand. This increase in affinity is believed to heighten theinteraction between these cells and their natural ligands, therebyfacilitating such interaction and encouraging cellular response to suchinteraction. (Khavinson et al., WO 94/20063.)

SUMMARY OF THE INVENTION

[0006] This invention provides analogs of L-Glu-L-Trp having severaladvantages over the parent compound. In these analogs, the nitrogen ofthe indole ring of tryptophan is replaced by a carbon. The carbon can besubstituted with a variety of groups. Preferably, the carbon issaturated with hydrogen. L-Glu-L-Trp has the structure of formula 1:

[0007] The compounds of this invention have the structure of formula 2:

[0008] wherein X and Y are independently selected from H, lower alkyls,esters, amides, halides, carbohydrates or oligodideoxyribose groups, or,together can be a ketone group. The bond between X or Y and the carboncan be non-hydrolyzable. In that case, X or Y have a mass of less thanabout 500 D, preferably less than about 100 D. The bond between X or Yand the carbon can be hydrolyzable. In that case, any derivatizationwill result in an analog compound that, when exposed to water or to anenzyme that breaks a hydrolyzable bond, will convert or transform to ahydrate or ketone. Such forms are active.

[0009] These modifications to the indole ring provide severaladvantages. First, the analog is more resistant to oxidation, resultingin a more stable product. Second, the compound has higher lipidophilicqualities, allowing for better transport across lipid membranes, e,g.,the blood brain barrier. Third, the analogs are resistant to degradationby enzymes as compared to the parent tryptophan compound, allowing forlonger and higher serum levels. Fourth, the analogs have high solubilityin aqueous solutions, and rapid transport across the mucous membranes,allowing for high bioavailability. Fifth, the charge and spacialdistribution characteristics are similar to parent tryptophan analog,allowing for similar if not even greater biologic activity because ofthe greater stability in structure.

[0010] As an immunomodulator, the compounds of this invention areeffective in doses of about 1 ,μg/kg to about 1000 μg/kg, preferablyabout 10 μg/kg to about 100 μg/kg. As an inhibitor of angiogenesis, thecompounds of this invention are effective in doses of about 50 μg/kg toabout 100 mg/kg, preferably about 100 μg/kg to about 10 mg/kg.

DETAILED DESCRIPTION OF THE INVENTION

[0011] I. Analogs of L-Glu-L-Trp

[0012] The analog compounds of this invention are selected fromcompounds having the following structures:

[0013] (a) a compound of formula 2;

[0014] (b) a cyclic form of the compound of formula 2;

[0015] (c) a linear or cyclic polymer of the compound of formula 2, thepolymer being no more than a 10-mer;

[0016] (d) an analog of any of the foregoing wherein the Glu moiety isreplaced by an Ile moiety or a Leu moiety; and

[0017] (e) a derivative of any of the foregoing compounds whichhydrolyses in aqueous solution into any of the foregoing compounds.

[0018] Compounds whose structure include Glu-“Trp analog” have bestactivity as inhibitors of angiogenesis.

[0019] Regarding cyclized forms of the compound, it is well known in theart of chemistry that peptides frequently exist in solution inequilibrium between linear and cyclized states, equilibrium favoring thelinear state. Therefore, in the blood, cyclic L-Xaa-L-Trp (Xaa beingselected from Glu, Leu or Ile) would tend to equilibrate into the linearform. Regarding linear or cyclic polymers of L-Xaa-L-Trp, onceintroduced into the body, these compounds undergo proteolyticdegradation, thereby releasing the most active form of the compound,L-Xaa-L-Trp.

[0020] Derivatives of L-Glu-L-Trp also are useful in the treatments ofthis invention. In one embodiment, a derivative is a pharmaceuticallyacceptable salt of the above compounds. A “pharmaceutically acceptablesalt” is a salt that can be formulated into a compound forpharmaceutical use including, e.g., metal salts (sodium, potassium,magnesium, calcium, etc.) and salts of ammonia or organic amines.

[0021] In another embodiment, a derivative is an analog in which thereactive terminal amine or carboxyl groups are derivatized with amides,imides, esters, anhydrides, ethers, methyl or ethyl-alkyl esters, alkyl,aryl or mixed alkyl/aryl moieties in which the formula weight of theentire compound is less than about 5000 Daltons or less than about 1000Daltons. Such derivatives are expected to equilibrate into the activeform by, for example, hydrolysis in the body.

[0022] II. Pharmaceutical Compositions and Modes of Delivery

[0023] The compounds of this invention preferably are delivered aspharmaceutical compositions. “Pharmaceutical composition” refers to acomposition suitable for pharmaceutical use in a subject. Thepharmaceutical compositions of this invention comprise apharmacologically effective amount of a compound of the invention and apharmaceutically acceptable carrier. “Pharmaceutically acceptablecarrier” refers to any of the standard pharmaceutical carriers, buffers,and excipients, such as a phosphate buffered saline solution, 5% aqueoussolution of dextrose, and emulsions, such as an oil/water or water/oilemulsion, and various types of wetting agents and/or adjuvants. Suitablepharmaceutical carriers and formulations are described in Remington'sPharmaceutical Sciences, 19th Ed. (Mack Publishing Co., Easton, 1995).Preferred pharmaceutical carriers depend upon the intended mode ofadministration of the active agent.

[0024] The compounds of the invention can be formulated foradministration in a variety of ways. Typical routes of administrationinclude both enteral and parenteral. These include, without limitation,subcutaneous, intramuscular, intravenous, intraperitoneal,intramedullary, intrapericardiac, intrabursal, oral, sublingual, ocular,nasal, topical, transdermal, transmucosal, or anal. The mode ofadministration can be, e.g., via swallowing, inhalation, injection ortopical application to a surface (e.g., eyes, mucus membrane, skin).

[0025] Particular formulations typically are appropriate for specificmodes of administration. Various contemplated formulations include, forexample, aqueous solutions, solid formulations, aerosol, gas, vapor ordry powder formulations and transdermal formulations.

[0026] A. Aqueous Solutions for Enteral, Parenteral Or TransmucosalAdministration

[0027] Examples of aqueous solutions include, for example, water,saline, phosphate buffered saline, Hank's solution, Ringer's solution,dextrose/saline, glucose solutions and the like. A preferred carrier fordelivery of the tryptophan-containing compounds of this invention isnormal (0.09%) saline solution.

[0028] The compositions can contain pharmaceutically acceptableauxiliary substances as required to approximate physiologicalconditions, such as buffering agents, tonicity adjusting agents, wettingagents, detergents and the like. Additives can also include additionalactive ingredients such as bactericidal agents, or stabilizers. Forexample, the solution can contain sodium acetate, sodium lactate, sodiumchloride, potassium chloride, calcium chloride, sorbitan monolaurate ortriethanolamine oleate. These compositions can be sterilized byconventional, well-known sterilization techniques, or can be sterilefiltered. The resulting aqueous solutions can be packaged for use as is,or lyophilized, the lyophilized preparation being combined with asterile aqueous solution prior to administration.

[0029] Aqueous solutions are appropriate for injection (e.g. intravenousinjection). Aqueous solutions also are useful for enteral administrationas tonics and administration to mucous or other membranes as, e.g., noseor eye drops. The composition can contain the compound in an amount ofabout 1 μg/ml to about 10 mg/ml, more preferably about 10 μg/ml to about1 mg/ml, e.g., about 100 μg/ml.

[0030] B. Solid and Other Non-Aqueous Compositions for Enteral orTransdermal Delivery

[0031] Solid compositions are appropriate for enteral administration.They can be formulated in the form of, e.g., pills, tablets, powders orcapsules. For solid compositions, conventional solid carriers can beused which include, for example, pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharin, talcum,cellulose, glucose, sucrose, magnesium carbonate, and the like. For oraladministration, a pharmaceutically acceptable nontoxic composition isformed by incorporating any of the normally employed excipients, such asthose carriers previously listed.

[0032] The carrier can be selected from various oils including those ofpetroleum, animal, vegetable or synthetic origin, for example, peanutoil, soybean oil, mineral oil, sesame oil, and the like. Suitablepharmaceutical excipients include starch, cellulose, talc, glucose,lactose, sucrose, gelatin, maltose, rice, flour, chalk, silica gel,magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk, glycerol, propylene glycol, water, ethanol,and the like.

[0033] A unit dosage form, such as a tablet, can have about 1 μg toabout 100 mg of the compound.

[0034] C. Topical Administration for Transdermal or TransmucosalDelivery

[0035] Systemic administration can also be by transmucosal ortransdermal means. Transmucosal delivery is particularly attractive fortreatment of HIV infection because it can be self-delivered easily.

[0036] For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated can be used in theformulation. Such penetrations are generally known in the art, andinclude, for example, for transmucosal administration, bile salts andfusidic acid derivatives. In addition, detergents can be used tofacilitate permeation. Transmucosal administration can be through nasalsprays, for example, or using suppositories. Transdermal deliverysystems can include, e.g., patches.

[0037] For topical administration, the agents are formulated intoointments, creams, salves, powders and gels. In one embodiment, thetransdermal delivery agent can be DMSO. The compound can be administeredin a toothpaste.

[0038] D. Delivery by Inhalation

[0039] For inhalation, the compound is preferably administered in theform of an aerosol or mist. For aerosol administration, the compoundpreferably is supplied in finely divided form along with a surfactantand propellant.

[0040] The surfactant preferably is soluble in the propellant.Representative of such agents are the esters or partial esters of fattyacids containing from 6 to 22 carbon atoms, such as caproic, octanoic,lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleicacids with an aliphatic polyhydric alcohol or its cyclic anhydride suchas, for example, ethylene glycol, glycerol, erythritol, arabitol,mannitol, sorbitol, the hexitol anhydrides derived from sorbitol, andthe polyoxyethylene and polyoxypropylene derivatives of these esters.Mixed esters, such as mixed or natural glycerides, can be employed. Thesurfactant can constitute 0.1%-20% by weight of the composition,preferably 0.25%-5%.

[0041] The balance of the composition is ordinarily propellant.Liquefied propellants are typically gases at ambient conditions, and arecondensed under pressure. Among suitable liquefied propellants are thelower alkanes containing up to 5 carbons, such as butane and propane;and preferably fluorinated or fluorochlorinated alkanes. Mixtures of theabove can also be employed. In producing the aerosol, a containerequipped with a suitable valve is filled with the appropriatepropellant, containing the finely divided compounds and surfactant. Theingredients are thus maintained at an elevated pressure until releasedby action of the valve.

[0042] A nebulizer or aerosolizer device for administering compounds ofthis invention typically delivers a dose of about concentration ofbetween about 1 μg/m³ and about 10 mg/m³.

[0043] E. Other Formulations

[0044] In preparing pharmaceutical compositions of the presentinvention, it can be desirable to modify the complexes of the presentinvention to alter their pharmacokinetics and biodistribution. For ageneral discussion of pharmacokinetics, See, Remington's PharmaceuticalSciences, supra, Chapters 37-39. A number of methods for alteringpharmacokinetics and biodistribution are known to one of ordinary skillin the art. Examples of such methods include protection of the complexesin vesicles composed of substances such as proteins, lipids (forexample, liposomes), carbohydrates, or synthetic polymers.

[0045] The tryptophan-containing compounds of this invention also can beincorporated into foodstuffs. This includes solid foods, such as cerealsor chewing gums, as well as liquid foodstuffs, such as mixing thecompound with hot water as a tea, or incorporating it in any otherbeverage. The compound may be incorporated in a soap for transdermaldelivery during washing.

[0046] III. Prophylactic or Therapeutic Treatments

[0047] This invention provides methods for the prophylactic ortherapeutic treatment of a number of conditions, including immune systemdisorders, infections, tissue damage, toxemia or anemia during pregnancyand enhancement of vaccination.

[0048] “Infection” refers to the multiplication of a parasitic organism,e.g., a virus, in a cell or in the body. A subject is “infected” with anorganism if the subject has detectable amount of the organism orantibodies that specifically bind to the organism in their body. A“subject” of treatment is a mammal, including a human. Non-human animalssubject to diagnosis or treatment include, for example, domesticatedanimals such as cats. “Treatment” refers to prophylactic treatment ortherapeutic treatment. A “prophylactic” treatment is a treatmentadministered to a subject who does not exhibit signs of a disease orexhibits only early signs for the purpose of decreasing the risk ofdeveloping pathology. A “therapeutic” treatment is a treatmentadministered to a subject who exhibits signs of pathology for thepurpose of diminishing or eliminating those signs.

[0049] IV. Treatments of Immunodeficient, Immunodepressed or HyperactiveImmune States

[0050] This invention provides methods for treating an immune systemdisorder, e.g., an immunodeficient, immunodepressed or hyperactiveimmune state, in subject, e.g., human. The method comprisesadministering to the subject a pharmacologically effective amount of acompound of this invention. In one embodiment, the hyperactive immunestate is an autoimmune disease. In one embodiment, the subject suffersfrom eczema, psoriasis, allergy or bronchial asthma. In anotherembodiment, the subject has been subject to thymectomy. In anotherembodiment, the subject has an immunodepressed state resulting fromexposure to radiation, e.g. in the treatment of cancer.

[0051] V. Treatments of Infectious Diseases

[0052] This invention provides methods for the treatment of aninfectious disease in an animal subject. The method comprisesadministering to the subject a pharmacologically effective amount of acompound of this invention. The establishment of infection frequentlyinvolves a deficiency in the immune system. Therefore, normalizingimmune system function has the effect of decreasing the likelihood ofdeveloping infection or, once established, inhibiting infection. Also,the compounds of this invention are useful in inhibiting viralreplication, in particular, retroviral replication, in the body. Theinfection can be a viral infection, bacterial infection or parasiticinfection.

[0053] In one embodiment, the disease results from infralymphaticinfection, a gynecological infection or a skin infection. In anotherembodiment, the disease is lymphangitis, an acute respiratory disease,sinusitis or parsinusitus, Otitis media, conjunctivitis, uveitis,keratitis, dental caries, gingival disease, is periapical granuloma. Inanother embodiment, the infection is a viral disease selected fromherpes infection, herpes Type I or Type II infection, Herpes Zosterinfection, influenza virus infection Type A or Type B, Hepatitis A orHepatitis B infection or hemorrhagic dengue fever. In another embodimentthe disease is Hansen's disease, typhus of the para A or B category,tuberculosis of the lung, yersenia, pseudo-tuberculosis or Shigelladysentery. In another embodiment, the disease is malaria.

[0054] VI. Treatment of Tissue Damage

[0055] This invention provides a method for the therapeutic treatment oftissue damage in an animal subject. The method comprises administeringto the subject a pharmacologically effective amount of a compound of theinvention.

[0056] In one embodiment, the tissue damage results from a burn or frostbite. In another embodiment, the tissue is corneal tissue.

[0057] VII. Treatment of Toxemia or Anemia During Pregnancy

[0058] This invention provides a method for treating toxemia or anemiain an animal subject during pregnancy. The method comprisesadministering to the subject a pharmacologically effective amount of acompound of this invention.

[0059] VIII. Treatment for Enhancing the Effect of Vaccination

[0060] This invention provides a method for enhancing the effect of avaccination to a disease in an animal subject. The method comprising thestep of administering to the subject a pharmacologically effectiveamount of a compound of this invention.

[0061] IX. Treatment of Pathological Conditions Involving PathologicNeovascularization

[0062] This invention provides a method of treating a subject having apathologic condition involving neovascularization. The method involvesadministering a pharmacologically effective amount of a compound of thisinvention.

[0063] In one embodiment, the condition is hemangioma. In anotherembodiment the condition is vascularized malignant tumor or vascularizedbenign tumor. In another embodiment, the condition is neovascularizationin post-recovery cerebrovascular accident; neovascularization due tohead trauma; restenosis following angioplasty; or neovascularization dueto heat or cold trauma. In another embodiment, condition isneovascularization associated with substance-induced neovascularizationof the liver, angiogenic dysfunction related to an excess of hormone;neovascular sequelae of diabetes; neovascular sequelae to hypertension;or chronic liver infection. In another embodiment the subject suffersfrom AIDS and Kaposi's sarcoma.

[0064] The present invention provides novel analogs of L-Glu-L-Trp andmethods for their use. While specific examples have been provided, theabove description is illustrative and not restrictive. Many variationsof the invention will become apparent to those skilled in the art uponreview of this specification. The scope of the invention should,therefore, be determined not with reference to the above description,but instead should be determined with reference to the appended claimsalong with their full scope of equivalents.

[0065] All publications and patent documents cited in this applicationare incorporated by reference in their entirety for all purposes to thesame extent as if each individual publication or patent document were soindividually denoted. By their citation of various references in thisdocument Applicants do not admit that any particular reference is “priorart” to their invention.

What is claimed is:
 1. An analog compound of L-Glu-L-Trp of the structure: (a) a compound of formula 2; (b) a cyclic form of the compound of formula 2; (c) a linear or cyclic polymer of the compound of formula 2, the polymer being no more than a 20-mer; (d) an analog of any of the foregoing wherein the Glu moiety is replaced by an Ile moiety or a Leu moiety; and (e) a derivative of any of the foregoing compounds which hydrolyses in aqueous solution into any of the foregoing compounds.
 2. The compound of claim 1 having the structure of part (a), or a pharmaceutically acceptable salt thereof.
 3. The compound of claim 2 wherein X and Y are both H.
 4. A pharmaceutical composition comprising an amount of a compound of claim 1 effective for immunomodulation and a pharmaceutically acceptable career.
 5. The pharmaceutical composition of claim 4 comprising 0.001% to 0.01% by weight of the compound.
 6. The pharmaceutical composition of claim 4 in the form of an injectable solution, a tablet, a suppository or a capsule.
 7. The pharmaceutical composition of claim 4 in the form of an eye film, an inhalant, a mucosal spray, a toothpaste, an ointment or a water soluble based cream.
 8. The pharmaceutical composition of claim 4 in unit dosage form comprising about 10 μg to about 100 μg of the compound.
 9. A method for treating an immunodeficient, immunodepressed or hyperactive immune state in an animal subject comprising administering to the subject a pharmacologically effective amount of a compound of claim
 1. 10. The method of claim 9 wherein the subject is a human.
 11. The method of claim 10 wherein the compound has the structure of claim 1, part (a), or a pharmaceutically acceptable salt thereof.
 12. The method of claim 11 wherein X and Y are both H.
 13. The method of claim 9 wherein the subject suffers from an immunodeficient or immunodepressed state.
 14. The method of claim 9 wherein the subject suffers from eczema, psoriasis, allergy or bronchial asthma.
 15. The method of claim 13 wherein the subject has been subject to thymectomy.
 16. The method of claim 13 wherein the subject has an immunodepressed state resulting from exposure to radiation.
 17. The method of claim 13 wherein the subject has an immunodepressed state resulting from exposure to radiation in the treatment of cancer.
 18. A method for the treatment of an infectious disease in an animal subject comprising administering to the subject a pharmacologically effective amount of a compound of claim
 1. 19. The method of claim 18 wherein the subject is a human.
 20. The method of claim 19 wherein the compound has the structure of claim 1, part (a), or a pharmaceutically acceptable salt thereof.
 21. The method of claim 20 wherein X and Y are both H.
 22. The method of claim 19 wherein the disease results from viral infection, bacterial infection or parasitic infection.
 23. The method of claim 19 wherein the disease results from infralymphatic infection, a gynecological infection or a skin infection.
 24. The method of claim 19 wherein the disease is lymphangitis, an acute respiratory disease, sinusitis or parsinusitus, Otitis media, conjunctivitis, uveitis, keratitis, dental caries, gingival disease, is periapical granuloma.
 25. The method of claim 22 wherein the infection is a viral disease selected from herpes infection, herpes Type I or Type II infection, Herpes Zoster infection, influenza virus infection Type A or Type B, Hepatitis A or Hepatitis B infection or hemorrhagic dengue fever.
 26. The method of claim 22 wherein the disease is Hansen's disease, typhus of the para A or B category, tuberculosis of the lung, yersenia, pseudo-tuberculosis or Shigella dysentery.
 27. The method of claim 22 wherein the disease is malaria.
 28. A method for the therapeutic treatment of tissue damage in an animal subject comprising administering to the subject a pharmacologically effective amount of a compound of claim
 1. 29. The method of claim 28 wherein the subject is a human.
 30. The method of claim 29 wherein the compound has the structure of claim 1, part (a), or a pharmaceutically acceptable salt thereof.
 31. The method of claim 30 wherein X and Y are both H.
 32. The method of claim 30 wherein the tissue damage results from a burn or frost bite.
 33. The method of claim 30 wherein the tissue is corneal tissue.
 34. A method for treating toxemia or anemia in an animal subject during pregnancy comprising administering to the subject a pharmacologically effective amount of a compound of claim
 1. 35. The method of claim 34 wherein the subject is a human.
 36. The method of claim 35 wherein the compound has the structure of claim 1, part (a), or a pharmaceutically acceptable salt thereof.
 37. The method of claim 36 wherein X and Y are both H.
 38. A method for enhancing the effect of a vaccination to a disease in an animal subject comprising the step of administering to the subject a pharmacologically effective amount of a compound of claim
 1. 39. The method of claim 38 wherein the subject is a human.
 40. The method of claim 39 wherein the compound has the structure of claim 1, part (a), or a pharmaceutically acceptable salt thereof.
 41. The method of claim 40 wherein X and Y are both H.
 42. A method of treating a subject having a pathologic condition involving neovascularization comprising administering a pharmacologically effective amount of a compound of claim
 1. 43. The method of claim 42 wherein the subject is a human.
 44. The method of claim 43 wherein the compound has the structure of claim 1, part (a), or a pharmaceutically acceptable salt thereof.
 45. The method of claim 44 wherein X and Y are both H.
 46. The method of claim 43 wherein the condition is hemangioma.
 47. The method of claim 43 wherein the condition is vascularized malignant tumor or vascularized benign tumor.
 48. The method of claim 43 wherein the condition is neovascularization in post-recovery cerebrovascular accident; neovascularization due to head trauma; restenosis following angioplasty; or neovascularization due to heat or cold trauma.
 49. The method of claim 43 wherein the condition is neovascularization associated with substance-induced neovascularization of the liver, angiogenic dysfunction related to an excess of hormone; neovascular sequelae of diabetes; neovascular sequelae to hypertension; or chronic liver infection.
 50. The method of claim 43 comprising administering to the subject a dose of about 50 μg/kg to about 100 mg/kg.
 51. The method of claim 50 wherein the effective amount is about 1 μg/kg to about 50 μg/kg body weight.
 52. The method of claim 43 wherein the compound is administered intramuscularly, intravenously or intranasally.
 53. The method of claim 43 wherein the subject suffers from AIDS and Kaposi's sarcoma.
 54. A method of treating HIV infection in a subject comprising administering to the subject a pharmacologically effective amount of a compound of claim
 1. 55. The method of claim 54 wherein the compound has the structure of claim 1, part (a), or a pharmaceutically acceptable salt thereof.
 56. The method of claim 55 wherein X and Y are both H.
 57. The method of claim 54 wherein the treatment is a therapeutic treatment for a person who is infected with HIV.
 58. The method of claim 54 wherein the treatment is a prophylactic treatment for a person who shows no sign of infection with HIV. 